Figure 5.

NAMs Causing Upstream Rewiring

(A) Upstream rewiring mutations will cause a new kinase (from K1 to K2) to phosphorylate the mutant protein (S, red). By plotting the probability of both kinases to phosphorylate the wild-type and mutant variants of the protein, we can visualize, quantify, and compare different upstream rewiring mutations.

(B) The rewiring power and the rewiring angle can be computed by considering the necessary trajectory that the mutation causes (from the “origin” right-bottom triangle to the “destination” left-top triangle). The rewiring power is equivalent to the magnitude of the vector and measures the rewiring capacity of the mutation. The rewiring angle is the angle of the vector from the diagonal and distinguishes whether the rewiring effect is mainly driven by kinase resignation (i.e., a loss of phosphorylating ability of the wild-type kinase, angle >45°), depicted in blue, or by kinase take-over (i.e., an increase of phosphorylation ability of a new kinase, angle <45°), depicted in green. The three examples illustrate how three different mutations (A–C) can lead to different outcomes, such as the same rewiring power but different main driving force (A and B) or the same driving force but different magnitude (B and C).

(C) Illustration of the two main driving processes that cause upstream rewiring, namely the reduced ability of the original kinase to phosphorylate the new mutant substrate variant (resignation) and the increased ability of a second kinase to phosphorylate the mutant substrate protein (take-over).

(D) Representation of all the upstream rewiring mutations identified in the global repository of somatic mutations at different distances relative to the phosphorylation site (from five residues before a phosphorylation site, P−5, to five residues after a phosphorylation site, P+5). Rewiring events mainly driven by resignation are shown in blue and those mainly driven by take-over are shown in green.

(E) Quantification of the percentage of mutations leading to upstream rewiring depending on their position relative to the phosphorylation site.

(F) Assessment of the median magnitude of rewiring for mutations based on their position relative to the phosphorylation site.

(G) The median rewiring angle (orange and yellow bars) and the ratio of take-over over resignation rewiring mutations (gray line) conditioned on the position of the mutation relative to the phosphorylation site.

See also Figure S5.